β-arrestin1-biased β1-adrenergic receptor signaling regulates microRNA processing.

Published

Journal Article

RATIONALE: MicroRNAs (miRs) are small, noncoding RNAs that function to post-transcriptionally regulate gene expression. First transcribed as long primary miR transcripts (pri-miRs), they are enzymatically processed in the nucleus by Drosha into hairpin intermediate miRs (pre-miRs) and further processed in the cytoplasm by Dicer into mature miRs where they regulate cellular processes after activation by a variety of signals such as those stimulated by β-adrenergic receptors (βARs). Initially discovered to desensitize βAR signaling, β-arrestins are now appreciated to transduce multiple effector pathways independent of G-protein-mediated second messenger accumulation, a concept known as biased signaling. We previously showed that the β-arrestin-biased βAR agonist, carvedilol, activates cellular pathways in the heart. OBJECTIVE: Here, we tested whether carvedilol could activate β-arrestin-mediated miR maturation, thereby providing a novel potential mechanism for its cardioprotective effects. METHODS AND RESULTS: In human cells and mouse hearts, carvedilol upregulates a subset of mature and pre-miRs, but not their pri-miRs, in β1AR-, G-protein-coupled receptor kinase 5/6-, and β-arrestin1-dependent manner. Mechanistically, β-arrestin1 regulates miR processing by forming a nuclear complex with hnRNPA1 and Drosha on pri-miRs. CONCLUSIONS: Our findings indicate a novel function for β1AR-mediated β-arrestin1 signaling activated by carvedilol in miR biogenesis, which may be linked, in part, to its mechanism for cell survival.

Full Text

Duke Authors

Cited Authors

  • Kim, I-M; Wang, Y; Park, K-M; Tang, Y; Teoh, J-P; Vinson, J; Traynham, CJ; Pironti, G; Mao, L; Su, H; Johnson, JA; Koch, WJ; Rockman, HA

Published Date

  • February 28, 2014

Published In

Volume / Issue

  • 114 / 5

Start / End Page

  • 833 - 844

PubMed ID

  • 24334028

Pubmed Central ID

  • 24334028

Electronic International Standard Serial Number (EISSN)

  • 1524-4571

Digital Object Identifier (DOI)

  • 10.1161/CIRCRESAHA.114.302766

Language

  • eng

Conference Location

  • United States